# US 2014/0087002 A1 · Autologous Lymph Node Transfer In Combination With VEGF-C Or VEGF-D Growth Factor Therapy to Treat Lymphedema And To Improve Reconstructive Surgery

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- Number: US 2014/0087002 A1
- Document ID: US20140087002A1
- Status: Published application
- Kind: A1
- Application number: 13/624,145
- Filed: 2012-09-21
- Published: 2014-03-27
- Earliest claimed: 2012-09-21
- Assignees: Laurantis Pharma Oy
- Applicants: Laurantis Pharma Oy
- Inventors: ANNE SAARISTO
- Web page: https://patentgrep.com/patent/US20140087002A1

## CPC

- A61K 35/26: Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
- A61K 35/36: Skin; Hair; Nails; Sebaceous glands; Cerumen; Epidermis; Epithelial cells; Keratinocytes; Langerhans cells; Ectodermal cells (islets of Langerhans A61K35/39)
- A61K 38/1866: {Vascular endothelial growth factor [VEGF]}
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Materials and methods are provided to improve survival of lymph nodes and integration of lymph nodes into a lymphatic network, following lymph node transplantation. The treatment or prevention of lymphedema is also addressed. A method of lymph node transfer includes transferring or transplanting a lymph node or lymph node fragment in a mammalian subject; and administering a composition comprising an agent selected from the group consisting of Vascular Endothelial Growth Factor C (VEGF-C) polynucleotides, VEGF-C polypeptides, Vascular Endothelial Growth Factor D (VEGF-D) polynucleotides, and VEGF-D polypeptides to a perinodal site within 20 cm of the lymph node or lymph node fragment. In certain embodiments, the agent is present in the composition in an amount effective to promote survival of the lymph node and integration of the lymph node into a lymphatic network in the mammalian subject, at the site of transfer or transplantation.

## Claims

### Claim 1

A method of lymph node transfer comprising:
transferring or transplanting a lymph node or lymph node fragment in a mammalian subject; and
administering a composition comprising an agent selected from the group consisting of Vascular Endothelial Growth Factor C (VEGF-C) polynucleotides, VEGF-C polypeptides, Vascular Endothelial Growth Factor D (VEGF-D) polynucleotides, and VEGF-D polypeptides, to a non-lymph node tissue in a perinodal site within 20 cm of the lymph node or lymph node fragment;
wherein the agent is present in said composition in an amount effective to promote survival of the lymph node and integration of the lymph node into a lymphatic network in the mammalian subject, at the site of transfer or transplantation.

### Claim 2 (depends on 1)

A method of treating or inhibiting lymphedema in a mammalian subject comprising:
performing a surgery on a mammalian subject according to claim 1 that comprises transferring or transplanting a lymph node or lymph node fragment in the mammalian subject according to claim 1 to a site at which the subject is experiencing lymphedema, or is at risk for lymphedema.

### Claim 3

A method of reducing the incidence or severity of infection associated with a reconstructive surgery comprising:
performing reconstructive surgery on a mammalian subject, said surgery including transferring or transplanting a lymph node or lymph node fragment; and
administering a composition comprising an agent selected from the group consisting of Vascular Endothelial Growth Factor C (VEGF-C) polynucleotides, VEGF-C polypeptides, Vascular Endothelial Growth Factor D (VEGF-D) polynucleotides, and VEGF-D polypeptides, to a non-lymph node tissue in a perinodal site within 20 cm of the lymph node or lymph node fragment, in an amount effective to promote survival of the lymph node and integration of the lymph node into a lymphatic network in the mammalian subject, at the site of transfer or transplantation.

### Claim 4 (depends on 1)

The method of claim 1 wherein the perinodal site is at a distance of between 0.5 mm and 20 cm from the lymph node or lymph node fragment.

### Claim 5 (depends on 1)

The method of claim 1, wherein the perinodal site comprises perinodal fat tissue.

### Claim 6 (depends on 1)

The method of claim 1, comprising transferring or transplanting at least one whole lymph node.

### Claim 7 (depends on 6)

The method of claim 6, wherein the lymph node or lymph node fragment is isogenic with the mammalian subject.

### Claim 8 (depends on 6)

The method of claim 6, wherein the lymph node or lymph node fragment is autologously transferred or transplanted from one location in the subject to another location in the same subject.

### Claim 9 (depends on 1)

The method of claim 1, wherein the administering is performed before the transferring or transplanting of the lymph node or lymph node fragment.

### Claim 10 (depends on 1)

The method of claim 1, wherein the administering is performed or repeated after surgically removing the lymph node or lymph node fragment from one location and before the transferring or transplanting.

### Claim 11 (depends on 1)

The method of claim 1, wherein the administering is performed or repeated after the transferring or transplanting of the lymph node or lymph node fragment.

### Claim 12 (depends on 1)

The method of claim 1, wherein the transferring or transplanting comprises transferring or transplanting a skin flap or skin graft in the mammalian subject, wherein the skin flap or skin graft comprises at least one lymph node or lymph node fragment, and the administering is to a perinodal site within the flap, within 20 cm of the lymph node or lymph node fragment.

### Claim 13 (depends on 12)

The method of claim 12, wherein the skin flap or skin graft is a microvascular free-flap.

### Claim 14 (depends on 12)

The method of claim 12, wherein the composition is administered in an amount effective to reduce edema or increase perfusion at the skin graft or skin flap, thereby improving the healing of the skin graft or skin flap.

### Claim 15 (depends on 12)

The method according to any claim 12, wherein the transferring or transplanting comprises a step of attaching the skin graft or skin flap tissue to the underlying tissue.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the attaching step includes surgical connection of blood vessels between the underlying tissue and the skin graft or skin flap.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the attaching is performed without use of an angiogenic polypeptide that binds VEGFR-1 or VEGFR-2.

### Claim 18 (depends on 12)

The method according to claim 12, further comprising contacting the skin graft or skin flap with an angiogenic growth factor.

### Claim 19 (depends on 15)

The method according to claim 15, wherein the underlying issue is breast tissue.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the skin graft or skin flap is attached in a breast augmentation, breast reduction, mastopexy, or gynecomastia procedure.

### Claim 21 (depends on 12)

The method according to claim 12, wherein the skin graft is a split thickness, full thickness, or composite graft; and wherein the skin flap is a local flap, a regional flap, musculocutaneous flap, an osteomyocutaneous flap, or a soft tissue flap.

### Claim 22 (depends on 1)

The method according to claim 1, wherein the agent comprises a VEGF-C polynucleotide that encodes a VEGF-C polypeptide.

### Claim 23 (depends on 22)

The method according to claim 22, wherein said VEGF-C polynucleotide further encodes a heparin-binding domain in frame with the VEGF-C polypeptide.

### Claim 24 (depends on 22)

The method according to claim 22, wherein said polynucleotide further comprises a nucleotide sequence encoding a secretory signal peptide, wherein the sequence encoding the secretory signal peptide is connected in-frame with the sequence that encodes the VEGF-C polypeptide.

### Claim 25 (depends on 24)

The method according to claim 24, wherein the polynucleotide further comprises a promoter sequence operably connected to the sequence that encodes the secretory signal sequence and VEGF-C polypeptide, wherein the promoter sequence promotes transcription of the sequence that encodes the secretory signal sequence and the VEGF-C polypeptide in cells of the mammalian subject.

### Claim 26 (depends on 22)

The method according to claim 22, wherein the agent comprises a gene therapy vector that comprises the VEGF-C polynucleotide.

### Claim 27 (depends on 26)

The method according to claim 26, wherein the gene therapy vector comprises an adenoviral or adeno-associated viral vector.

### Claim 28 (depends on 27)

The method according to claim 27, wherein the gene therapy vector is AdApt VEGF-C (SEQ ID NO: 5).